tbuckley/cabot-search huggingface dataset:
Abstract 3044: <i>C. albicans</i> infection mediates upper gastrointestinal tract malignancy independently of Il17a in an APECED-like mouse model
Authors: Feng Zhu, Quynh T. Phan, Elise M. Ferre, Jami Willette-Brown, Rosalba Salcedo, Tsai-Wei Shen, Yu Fan, Yongmei Zhao, Monika Mehta, Daoud Meerzaman, Bao Tran, Giorgio Trinchieri, Michail S. Lionakis, Scott G. Filler, Yinling Hu
Journal: Cancer Research (2022)

Abstract Patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) develop chronic mucocutaneous candidiasis during childhood and about 10% of senior patients develop upper GI tract squamous cell carcinoma (SCC), suggesting that C. albicans infection may be relevant to the cause of SCC development in APECED patients. In this study, we investigated the role of C. albicans infection in upper GI tract SCC development using an APECED-like IKKα kinase-dead (KA/KA) mouse model. We found that KA/KA mice developed upper GI tract SCC after oral infection of WT C. albicans weekly for three months. Interestingly, while upper GI tract SCC development in C. albicans - infected KA/KA mice is IL-17a-independent, EGFR pathway plays an important role in C. albicans infection-mediated tumorigenesis in KA/KA mice, as evidenced by significantly lower SCC incidence in the upper GI tract of KA/KA mice infected with Als3Δ/Δ C. albicans. Moreover, upper GI tract SCCs from WT C. albicans-infected KA/KA mice exhibited robust p-EGFR and Ki67 signals. However, both p-EGFR and Ki67 signals were only mildly increased in upper GI tract of Als3Δ/Δ C. albicans-infected KA/KA mice compared to WT control mice. Meanwhile, EGFR inhibition dramatically reduced C. albicans colonization in upper GI tract and the weight of stomach in KA/KA mice. Furthermore, we found that aberrant infiltrations of neutrophils and macrophages with significant inflammatory signatures were present in the upper GI tract SCCs in KA/KA mice. Interestingly, KA/KA neutrophils exhibited a defect in C. albicans killing capacity due to functional defects in ROS generation, degranulation, NETs formation, and apoptosis. We reasoned that KA/KA neutrophils’ inability in C. albicans killing capacity may further enhance the tumor-promoting microenvironment. Finally, whole genome sequencing data suggested that C. albicans infection may lead to genome instability. Currently we are investigating the role of neutrophil infiltration in C. albicans infection-mediated upper GI tract tumorigenesis. Citation Format: Feng Zhu, Quynh T. Phan, Elise M. Ferre, Jami Willette-Brown, Rosalba Salcedo, Tsai-Wei Shen, Yu Fan, Yongmei Zhao, Monika Mehta, Daoud Meerzaman, Bao Tran, Giorgio Trinchieri, Michail S. Lionakis, Scott G. Filler, Yinling Hu. C. albicans infection mediates upper gastrointestinal tract malignancy independently of Il17a in an APECED-like mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3044.
Mental Health Treatment Gap—The Implementation Problem as a Research Problem
Authors: Emma E. McGinty, Matthew D. Eisenberg
Journal: JAMA Psychiatry (2022)

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Abstract 1641: Evaluating <i>in vivo</i> efficacy of bi-functional fusion protein anti-PD-1-IL21 in humanized B-hIL21R mice and B-hPD-1/hIL21R mice
Authors: Ruili Lyu, Zhixia Li, Leila Kokabee, Jiawei Yao, Yanhui Nie, Chaoshe Guo
Journal: Cancer Research (2022)

Abstract Interleukin 21 (IL21) binding to its receptor IL21R, results in downstream activation of multiple signaling molecules, including JAK1, JAK3, STAT1, and STAT3. Intriguingly, IL21 has been implicated in both positively and negatively regulating immune responses in a cell-type specific manner, suggesting drug candidates that target IL21/IL21R signaling has therapeutic potential. Specifically, recent reports suggest that antibodies targeting PD-1 fused to IL-21 has a synergistic anti-tumor effect. To generate a suitable animal model for in vivo assessment of a human anti-PD-1-IL21 fusion protein, Biocytogen developed humanized PD-1 and IL21R mice (B-hIL21R mice and B-hPD-1/hIL21R mice) by replacing the murine Il21r and PD-1 gene with the human IL21R and PD-1 counterparts via homologous recombination. Our data shows that human IL21R was detectable in sorted cells from homozygous B-hIL21R and B-hPD-1/hIL21R mice, while human PD-1 was detectable in B-hPD-1/hIL21R mice compared to wild type mice. Furthermore, STAT3 phosphorylation in splenocytes was successfully induced with mouse IL21 or human IL21 in homozygous B-hIL21R mice. In addition, percentages of T cells, B cells, NK cells, DCs, granulocytes, monocytes, macrophages, CD8+ T cells, CD4+ T cells and Tregs in homozygous B-hIL21R mice and B-hPD-1/hIL21R mice were similar to those in wild type mice, demonstrating that introduction of human IL21R and PD-1 genes in place of its mouse counterpart does not change the overall development, differentiation or distribution of these cell types. To evaluate in vivo efficacy of anti-mPD-1-hIL21 and anti-hPD-1-hIL21 fusion proteins, mouse colon adenocarcinoma MC38 cells were subcutaneously implanted into homozygous B-hIL21R mice (female, 6-7-week-old, n=6) or B-hPD-1/hIL21R mice (female, 6-7-week-old, n=6). Mice were grouped and treated when tumor volume reached approximately 100 mm3. Results showed that anti-PD-1-hIL21 fusion proteins were efficient at inhibiting tumor growth in B-hIL21R and B-hPD-1/hIL21R mice. Altogether, B-hIL21R and B-hPD-1/hIL21R mice are promising humanized mouse models for preclinical in vivo studies to assess novel drug candidates. Keywords: IL21/IL21R, humanized mice, fusion protein Citation Format: Ruili Lyu, Zhixia Li, Leila Kokabee, Jiawei Yao, Yanhui Nie, Chaoshe Guo. Evaluating in vivo efficacy of bi-functional fusion protein anti-PD-1-IL21 in humanized B-hIL21R mice and B-hPD-1/hIL21R mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1641.
<i>BCL6</i>, a key oncogene, in the placenta, pre-eclampsia and endometriosis
Authors: Frank Louwen, Nina-Naomi Kreis, Andreas Ritter, Alexandra Friemel, Christine Solbach, Juping Yuan
Journal: Human Reproduction Update (2022)

Abstract BACKGROUND The key oncogene B-cell lymphoma 6 (BCL6) drives malignant progression by promoting proliferation, overriding DNA damage checkpoints and blocking cell terminal differentiation. However, its functions in the placenta and the endometrium remain to be defined. OBJECTIVE AND RATIONALE Recent studies provide evidence that BCL6 may play various roles in the human placenta and the endometrium. Deregulated BCL6 might be related to the pathogenesis of pre-eclampsia (PE) as well as endometriosis. In this narrative review, we aimed to summarize the current knowledge regarding the pathophysiological role of BCL6 in these two reproductive organs, discuss related molecular mechanisms, and underline associated research perspectives. SEARCH METHODS We conducted a comprehensive literature search using PubMed for human, animal and cellular studies published until October 2021 in the following areas: BCL6 in the placenta, in PE and in endometriosis, in combination with its functions in proliferation, fusion, migration, invasion, differentiation, stem/progenitor cell maintenance and lineage commitment. OUTCOMES The data demonstrate that BCL6 is important in cell proliferation, survival, differentiation, migration and invasion of trophoblastic cells. BCL6 may have critical roles in stem/progenitor cell survival and differentiation in the placenta and the endometrium. BCL6 is aberrantly upregulated in pre-eclamptic placentas and endometriotic lesions through various mechanisms, including changes in gene transcription and mRNA translation as well as post-transcriptional/translational modifications. Importantly, increased endometrial BCL6 is considered to be a non-invasive diagnostic marker for endometriosis and a predictor for poor outcomes of IVF. These data highlight that BCL6 is crucial for placental development and endometrium homeostasis, and its upregulation is associated with the pathogenesis of PE, endometriosis and infertility. WIDER IMPLICATIONS The lesson learned from studies of the key oncogene BCL6 reinforces the notion that numerous signaling pathways and regulators are shared by tumors and reproductive organs. Their alteration may promote the progression of malignancies as well as the development of gestational and reproductive disorders.
Abstract 1778: NR2F2 mediates cell growth and endocrine resistance in NF1 loss, ER+ breast cancer
Authors: Yanyan Cai, Peihua Zhao, Fan Wu, Hong Shao, Pedram Razavi, Guotai Xu, Maurizio Scaltriti, Sarat Chandarlapaty
Journal: Cancer Research (2022)

Abstract Genomic loss of in Neurofibromin 1 (NF1) is a recurrent mechanism driving metastatic progression and resistance to endocrine therapy in ER-positive breast cancer, via activation of the MAPK pathway, induction of cyclin D1 expression and modulation of estrogen receptor signaling. To identify specific mediators of tumor growth in NF1 mutant cancers, we performed a genetic knockout (KO) screen in isogenic WT and NF1 KO breast cancer cells. After employing stringent cutoff criteria, we found 28 genes that are specifically essential for NF1 KO cells but not WT cells. Among these genes, NR2F2, encoding an orphan nuclear receptor, was one of the top candidates. We validated that its loss significantly impaired the growth of multiple models of NF1 null, ER+ breast cancer. Loss of NF1 leads to the hyperactivation of Ras which sequentially activates multiple effector pathways, including the MAPK pathway and the PI3K-AKT pathway. We found that MAPK activation upon NF1 loss led to elevated NR2F2 expression levels. A negative correlation between NF1 and NR2F2 expression was further confirmed in public gene expression databases. These data suggested that induction of NR2F2 expression might be one mechanism that mediates endocrine resistance caused by NF1 loss. Consistently, we found that exogenous expression of NR2F2 could confer endocrine resistance while its knockout hypersensitized ER+ breast cancer cells to endocrine therapies and significantly attenuated NF1 loss induced resistance. RNA-seq analysis revealed that estrogen response gene sets were among the most enriched signatures upon NF1 KO, NR2F2 over-expression (OE) or NR2F2 KO. NF1 KO or NR2F2 OE decreased the expression of early estrogen response genes and impaired their E2-induced expression, most of which could be rescued by NR2F2 KO, suggesting a regulatory effect of NR2F2 on ER transcriptional activity. To further define these mechanisms, ongoing integrative analyses of NR2F2 qPlex-RIME, ER and NR2F2 ChIP-Sequencing and ATAC-Sequencing will be presented. Taken together, our studies identify NR2F2 as a MAPK driven transcript whose induction mediates endocrine resistance, and may serve as a novel therapeutic target to overcome anti-estrogen resistant breast cancer growth. Citation Format: Yanyan Cai, Peihua Zhao, Fan Wu, Hong Shao, Pedram Razavi, Guotai Xu, Maurizio Scaltriti, Sarat Chandarlapaty. NR2F2 mediates cell growth and endocrine resistance in NF1 loss, ER+ breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1778.
Abstract 5284: M1231 is a bispecific anti-MUC1xEGFR antibody-drug conjugate designed to treat solid tumors with MUC1 and EGFR co-expression
Authors: Christine Knuehl, Lars Toleikis, Julia Dotterweich, Jianguo Ma, Seema Kumar, Edith Ross, Claudia Wilm, Martina Schmitt, Hans Juergen Grote, Christiane Amendt
Journal: Cancer Research (2022)

Abstract Mucin 1 (MUC1) and epidermal growth factor receptor (EGFR) are co-expressed at high prevalence in multiple cancer indications such as non-small cell lung cancer (NSCLC), esophageal squamous cell carcinoma (ESCC), head and neck squamous cell carcinoma, triple negative breast cancer and ovarian cancer. Tumor-associated MUC1 is hypoglycosylated and exposes peptide epitopes within its extracellular domain, which are not accessible to antibodies in normal epithelial tissue. MUC1 co-localizes with EGFR as a result of loss of cell polarity in tumor cells. M1231 is a bispecific antibody-drug conjugate (ADC) based on a SEED (strand-exchange engineered domain)-antibody scaffold targeting tumor-associated MUC1 and EGFR. Sutro Biopharma’s cell free expression system Xpress CF+™ enables incorporation of non-natural amino acids at precise positions in the SEED-antibody for site-specific linker-payload conjugation. The cytotoxic payload of M1231 (SC209) is a hemiasterlin-related microtubule inhibitor. The cleavable linker (ValCit-PABA) maintained ADC stability in human plasma in vitro, ensuring low systemic payload release. Pre-clinical activity of M1231 was assessed in vitro in cancer cell lines and in vivo in NSCLC and ESCC patient-derived xenograft (PDX) models. M1231 inhibited tumor cell viability in vitro at sub-nanomolar IC50 values. The bispecific MUC1xEGFR antibody has demonstrated superior internalization and lysosomal trafficking compared to monospecific bivalent antibodies. Efficient ADC uptake resulted in superior antitumor activity of M1231 in PDX models compared to monospecific bivalent ADCs. M1231 demonstrated durable and dose-dependent antitumor activity in PDX models. Strong antitumor activity with complete regression was observed in NSCLC and ESCC PDX models following a single treatment of M1231. M1231 antitumor activity was associated with high target expression in NSCLC PDX models and was observed across a range of target expression levels in ESCC models. In summary, efficient payload delivery to tumor cells and strong antitumor activity of M1231 indicate that M1231 may have the potential to deliver an efficacy benefit to patients with tumors co-expressing MUC1 and EGFR. Citation Format: Christine Knuehl, Lars Toleikis, Julia Dotterweich, Jianguo Ma, Seema Kumar, Edith Ross, Claudia Wilm, Martina Schmitt, Hans Juergen Grote, Christiane Amendt. M1231 is a bispecific anti-MUC1xEGFR antibody-drug conjugate designed to treat solid tumors with MUC1 and EGFR co-expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5284.
Abstract 88: ATAD3A enhances head and neck cancer malignancy via mitochondrial ERK1/2 signaling
Authors: Liwei Lang, Reid Loveless, Zhaohui Qin, Peng Qiu, Chloe Shay, Yong Teng
Journal: Cancer Research (2022)

Abstract Targeting mitochondria as a cancer therapeutic strategy has attracted more and more attention in the recent years. ATAD3A is identified as a nuclear-encoded mitochondrial enzyme that regulates mitochondrial dynamics, cholesterol metabolism, and signal transduction. However, its impact and underlying regulatory mechanisms in cancers remain to be determined. We report here that ATAD3A is highly expressed in head and neck squamous cell carcinoma (HNSCC), where it plays a critical role in favoring tumor progression. Loss of ATAD3A expression dramatically incudes tumor regression in orthotopic tongue tumor-bearing mice, whereas gain of ATAD3A expression produces the opposite effects. Mechanistically, ATAD3A binds to ERK1/2 at HNSCC cell mitochondria in the presence of VDAC1, and this interaction is essential for the activation of mitochondrial ERK1/2 signaling. Most importantly, the ATAD3A-ERK1/2 signaling axis enhances HNSCC development in a Ras-independent manner and, thus, tumor suppression is more effectively achieved when ATAD3A and Ras signaling pathways are co-inhibited. These novel findings highlight the importance of activation of ATAD3A-ERK1/2 axis in cancer progression and suggest that combined targeting of ATAD3A and Ras signaling could potentiate anticancer activity for HNSCC treatment. Citation Format: Liwei Lang, Reid Loveless, Zhaohui Qin, Peng Qiu, Chloe Shay, Yong Teng. ATAD3A enhances head and neck cancer malignancy via mitochondrial ERK1/2 signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 88.
Abstract 5348: SEMA3C signaling confers resistance to Wnt Inhibition in glioblastoma
Authors: Jing Hao
Journal: Cancer Research (2022)

Abstract Background: Wnt signaling is widely dysregulated in cancer. The therapeutic potential of Wnt inhibitors appears promising in preclinical studies. However, they have uniformly failed clinical trials. How cancer cells develop Wnt inhibitor resistance is poorly understood. Current Wnt inhibitors are designed targeting either ligand or receptor. We hypothesized cancer cells will bypass ligand-receptor interaction through an unknown mechanism. We focused on the neurodevelopmental signaling program of Semaphorin 3C (Sema3C) that is upregulated in 85% of GBM and regulates glioma stem-cell-driven tumor progression. Methods: We analyzed the expression of Sema3C and TCF1 expression pattern in 32 human GBM samples by immunohistochemistry. GSC self-renewal was assessed by extreme limiting dilution, Edu incorporation, tumorsphere formation and cell survival assays in Sema3C silencing GSCs. Cell fractionation and immunofluorescence studies were performed to assess β-catenin sub-cellular localization in GSCs. GSC-derived mouse models were assessed for survival. Results: Porcupine inhibitor LGK974 reduced TCF1 expression in the GBM tumor mouse models, suggesting successful target engagement in vivo. However, it failed to prolong the overall survival. Sema3C expression strongly correlated with TCF1 expression in human GBM samples by immunohistochemical analysis. Genetic inhibition of Sema3C and TCF1 together prolonged animal survival more than either alone, indicating better control of Wnt pathway signaling with dual pathway blockade. Immunofluorescence and cell fractionation studies revealed that Sema3C signaling drove β-catenin nuclear accumulation. Sema3C regulates transactivation of Wnt target genes including TCF1, c-Myc and c-Met. Sema3C pathway activates Rac1. It is reported that Rac1 activates β-catenin and promotes β-catenin nuclear accumulation. In GSCs, constitutively active Rac1 restored β-catenin nuclear localization and rescued TCF1 and c-Myc down-regulation in the setting of Sema3C silencing. Sema3C can drive canonical Wnt signaling even when Wnt ligand secretion is blocked. Together, the data support that GSCs can escape Wnt inhibition through Sema3C and Rac1. Conclusions: Sema3C signaling drives canonical Wnt signaling, providing an escape mechanism for cancer cells despite Wnt ligand-receptor interruption. Sema3C-β-catenin signaling promotes GSC self-renewal and tumor progression. Upstream Wnt pathway inhibition alone is insufficient to control tumors. Our data provide a therapeutic strategy of dual blockade of Wnt and Sema3C pathways to provide clinically significant tumor control. Citation Format: Jing Hao. SEMA3C signaling confers resistance to Wnt Inhibition in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5348.
Abstract 1297: Chemotherapy-induced senescence activates robust, parallel programs of immune checkpoint expression that can be targeted with immunotherapy
Authors: Ashkan Shahbandi, Fang-Yen Chiu, Nathan A. Ungerleider, Ashlyn Y. Anderson, Heather L. Machado, Zachary F. Pursell, Raegan Kvadas, Sonia G. Rao, James G. Jackson
Journal: Cancer Research (2022)

Abstract We and others have previously shown that the breast cancers most difficult to eradicate with chemotherapy are TP53 wild-type, and these are among the most lethal breast cancers. For instance, chemotherapy-treated TNBC patients with TP53 wild-type tumors have a median overall survival of 45 months, vs 263 months for TP53 mutant tumors. Treatments fail to eradicate these cancers for two reasons: the tumor cells 1) avoid intrinsic cell death, and 2) escape immune clearance. We have shown that p53 drives a program of senescence that arrests the cell cycle to prevent intrinsic modes of cell death such as mitotic catastrophe, apoptosis and nutrient deprivation. However, it is not currently understood how breast cancer cells that enter senescence to survive chemotherapy escape immune clearance. Here, we show tumor cells from mice and human patients that survive chemotherapy activate complex programs of immune modulation. Surprisingly, the surviving, senescent tumor cells are highly enriched for many antigen presentation genes and positive regulators of T cell activation, suggesting they have switched from immunologically “cold” to “hot”. Unfortunately, these senescent tumors concurrently upregulate redundant expression of many T cell inhibitory checkpoint genes, including CD80 and PD-L1. scRNA-seq and cell imaging revealed that CD80 and PD-L1 each mark unique populations of cells in the treated tumor, typified by p53 signaling or interferon signaling, respectively. In p53 wild-type, syngeneic, orthotopic mouse mammary tumor models that recapitulate human breast cancer response to chemotherapy, treatment of tumors with chemotherapy followed by targeting of the PD-L1 and/or CD80 axes improved response, including complete eradication in some instances. Unfortunately, however, even combination strategies failed to elicit a cure in the majority of cases. Our findings reveal the formidable challenge of eliminating residual disease populated by senescent cells that express multiple redundant immune inhibitory pathways and suggest rational strategies are needed based on the specific checkpoint pathways expressed in residual disease. Citation Format: Ashkan Shahbandi, Fang-Yen Chiu, Nathan A. Ungerleider, Ashlyn Y. Anderson, Heather L. Machado, Zachary F. Pursell, Raegan Kvadas, Sonia G. Rao, James G. Jackson. Chemotherapy-induced senescence activates robust, parallel programs of immune checkpoint expression that can be targeted with immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1297.